For an estimated 12,000 American women of childbearing age, having a baby is a genetic game of Russian roulette. Due to a rare flaw in their eggs, their offspring run a significant risk of living short and painful lives, with bodies unable to make enough energy to grow properly.

Genetic engineering might help such women have healthy children. But even as some countries consider such advances, the techniques are proving controversial.

Genetic manipulation that involves combining material from the eggs of two different women was recently legalized in the United Kingdom. It is not allowed in the United States, where scientists want to start clinical trials and the Food and Drug Administration is weighing the issues involved in such technologies.

“The modifications are heritable, so everyone downstream in the family tree is at risk to inherit whatever modification you make,” says Dana Carroll, a biochemist at the University of Utah School of Medicine in Salt Lake City. “We need to have a broad discussion about this that engages people beyond scientists.”

The problem that scientists are trying to fix starts with an egg’s mitochondria, the tiny power plants in human cells that make energy. We inherit all of our mitochondria from our mothers. Floating in the liquid that fills our cells, mitochondria look like bacteria. In fact, most scientists think they are a bacterium that a single-celled primordial ancestor of ours engulfed a billion and a half years ago. They are, in effect, ancient aliens living within us.

Mitochondria have their own DNA, organized into a mere 37 genes — compared with the thousands of genes whose DNA determine a person’s eye color, height and other characteristics. In addition to making energy, mitochondrial DNA helps store calcium, aids the liver in breaking down toxins and performs other duties essential to health.

Juan Carlos Izpisua Belmonte, a biochemist at the Salk Institute in La Jolla, Calif., has seen how mutations in mitochondrial DNA can complicate pregnancy. He has been studying a woman in Barcelona who has errors in the mitochondria inside virtually all her cells.

Fortunately for her, mitochondria contain many copies of DNA, and she has enough error-free copies to keep her own cells healthy. Unfortunately, her eggs are a different story: Whether the mitochondria inside each of them has more good or bad DNA is a matter of chance. The health of any children she might bear would depend on which mitochondria they happen to inherit.

“Some eggs will acquire more good DNA, some eggs will acquire more bad DNA,” says Izpisua Belmonte. “It’s random.”

The woman rolled the dice several years ago by getting pregnant. Her son, a toddler now, almost certainly will not survive beyond his teens, according to J.M. Campistol, the family’s physician. He will spend his short life in a wheelchair, his body in pain and his brain racked by seizuresdue to what is called mitochondrial oxidative phosphorylation disorder. “There is no treatment,” Campistol says. “All we can do is try to keep him comfortable.”

Facing the loss of her son, the mother wants to have another child. She could chance another pregnancy. She could adopt, or she could arrange to mix her husband’s sperm with another woman’s egg, and have a child unrelated to her biologically.

Fortunately for science, the woman donated some of her eggs to Izpisua Belmonte, who has found a way to delete the flaw in her eggs’ mitochondria, though his technique has not yet been proved safe enough to be used on would-be mothers.

If proved safe, this approach could offer an alternative to techniques, recently legalized in the United Kingdom, that have proved controversial and are more technically difficult.

A problem of power

Women with mitochondrial problems — which are difficult to diagnose but can be revealed by lab tests — often opt to forgo getting pregnant. When testing reveals that a woman’s mitochondria have only a small amount of bad DNA, traditional in vitro fertilization techniques can be used: Doctors fertilize several eggs with sperm, allow them to divide into a few cells, test one or two of the cells from each embryo and implant the embryo that has the healthiest mitochondria in the woman’s uterus.

“If I were a woman carrying a relatively low proportion of these [mitochondria] mutants, I would do that first,” says Eric Shoubridge, a biochemist at McGill University in Montreal who studies mitochondria. “It’s really the best option.”

That’s not an option for the patient in Barcelona and others like her, who have so much bad DNA that all of their eggs stand a good chance of containing unhealthy mitochondria. For such women, Izpisua Belmonte hopes to create healthy eggs by essentially cutting out the defective DNA.

Cutting out the bad

He uses TALENs, or transcription activator-like effector nucleases. These molecules, borrowed from bacteria, work like little scissors and can be custom-made in a lab to recognize and cut out specific mutations.

To show that TALENs can differentiate between strands of DNA with different mutations, Izpisua Belmonte and colleagues injected the scissors into mouse eggs containing two kinds of mitochondrial DNA. The TALENs recognized a mutation on one kind and cut it into fragments while leaving the other DNA untouched.

Repeating the experiment with mitochondrial DNA donated by the mother in Barcelona and two other women, the researchers showed that they could destroy DNA that causes severe diseases while sparing the good DNA, they reported this spring in the journal Cell.

Whether a human egg engineered in this way could grow into a healthy baby remains to be shown. Some women’s eggs might not have enough good DNA to stay viable after eliminating all the bad DNA.

Another worry is that the TALENs might clip unintended targets in the DNA and thus possibly cause birth defects. “You have to worry about off-target effects,” says Carla Koelher, a biochemist who studies mitochondria at the University of California at Los Angeles. “That’s the big safety question here.”

Chinese scientists provided a powerful demonstration of this problem in a controversial experiment that recently made headlines. Junjiu Huang reported that he and colleagues at Sun Yat-sen University in Guangdong collected embryos that had been rejected by fertility clinics for having genetic problems — problems that would have kept them from growing into fetuses. He tried to cut out a gene that can cause fatal blood problems. But the microscopic scissors he injected went on a rampage, slashing pieces of healthy DNA.

Izpisua Belmonte says he wants to test his scissors, which are different from Huang’s, on nonviable discarded embryos; he believes his will be more selective.

‘Three-person’ babies

British scientists are looking at other ways to help women with problematic DNA give birth to healthy babies. Newcastle University neurologist Doug Turnbull and colleagues start with an egg donated by a woman who does not have a genetic mutation.

The researchers swap the nuclear DNA in that egg with nuclear DNA from the egg of a woman with abnormal mitochondria; her egg, now normal, is then fertilized and implanted in the prospective mother.

In a variation of this procedure, the researchers do the DNA swap after both eggs have been fertilized.

Either version of this mitochondrial replacement therapy is different from a standard donor-egg pregnancy because the embryos created would contain DNA from three people — most of it nuclear DNA controlling eye color, etc., from the parents and a tiny amount of mitochondrial DNA from the donor.

All of this extracting and transplanting is much more difficult than Izpisua Belmonte’s simple injection of TALENs to snip out bad mitochondria. Few clinics have the ability to pull it off.

Turnbull and his team performed a few dozen successful transplants on abnormal eggs collected from fertility clinics, as reported in 2010 in the journal Nature. And researchers from the Oregon Health & Science University who pioneered these techniques use them on eggs that grew into a couple of healthy rhesus macaque monkeys. They are awaiting FDA approval to begin clinical trials on humans.

Critics argue that more safety testing — to show, for instance, that mitochondrial DNA and nuclear DNA from different people can play well together — is needed before these techniques are used to make babies. But in February, one house of the British Parliament legalized Turnbull’s techniques. Clinics that meet licensing requirements — which have yet to be spelled out — could start doing transfers as early as October, Turnbull says. “There is a risk, but waiting also has consequences,” he says. “Many of the women we work with don’t have a lot of time to wait.” He notes that many are nearing the end of their prime childbearing years.

No one has ever been born from an egg that has received a mitochondrial transfer. But in the 1990s a fertility clinic did help create babies with mitochondria that didn’t come from the children’s parents.

Jacques Cohen at the Institute for Reproductive Medicine and Science of Saint Barnabas hospital in West Orange, N.J., wasn’t thinking about mitochondrial disorders. A fertility pioneer, he was hoping to improve success rates for in vitro fertilization. Guessing that some embryos failed to attach to the uterus because of problems in the fluid of their cells, his team injected 33 eggs with liquid from other people’s eggs. As they experimented to find something that might help, they didn’t care what was in the fluid, whether it was mitochondrial DNA or something else.

A woman in her 20s had come to the clinic after a series of miscarriages. Artificial insemination had failed. So had the hormone treatments and the standard in vitro fertilization. After an injection by Cohen’s team of liquid from another egg, she gave birth to a seemingly healthy baby. Genetic testing showed that some of the baby’s cells contained mitochondria transferred during the injection.

The girl recently celebrated her 16th birthday. She is a healthy, hard-working student who makes movies with her friends for fun, her mother says. She knows about her unusual cells, but it’s not a big deal for the family.

“It’s just borrowing a piece of someone else, like a heart transplant,” her mother says. “It doesn’t make her who she is.”

In 2001, the FDA began regulating what it called “gene therapy” involving human cells. The Saint Barnabas doctors felt that this effectively prohibited them from continuing their work. (The agency has not yet given anyone permission to manipulate mitochondria in human eggs and embryos.)

Because of the FDA action, the doctors stopped tracking the girl and 16 similar children. Cohen recently completed a follow-up study on their health; his findings have not yet been released.